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Research Article Free access | 10.1172/JCI118817

Arylsulfatase B activities and glycosaminoglycan levels in retrovirally transduced mucopolysaccharidosis type VI cells. Prospects for gene therapy.

C Fillat, C M Simonaro, P L Yeyati, J L Abkowitz, M E Haskins, and E H Schuchman

Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.

Find articles by Fillat, C. in: JCI | PubMed | Google Scholar

Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.

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Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.

Find articles by Yeyati, P. in: JCI | PubMed | Google Scholar

Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.

Find articles by Abkowitz, J. in: JCI | PubMed | Google Scholar

Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.

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Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.

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Published July 15, 1996 - More info

Published in Volume 98, Issue 2 on July 15, 1996
J Clin Invest. 1996;98(2):497–502. https://doi.org/10.1172/JCI118817.
© 1996 The American Society for Clinical Investigation
Published July 15, 1996 - Version history
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Abstract

Mucopolysacchariodosis type VI (MPS VI) is the lysosomal storage disorder caused by the deficient activity of arylsulfatase B (ASB; N-acetylgalactosamine 4-sulfatase) and the subsequent accumulation of the glycosaminoglycan (GAG), dermatan sulfate. In this study, a retroviral vector containing the full-length human ASB cDNA was constructed and used to transduce skin fibroblasts, chondrocytes, and bone marrow cells from human patients, cats, or rats with MPS VI. The ASB vector expressed high levels of enzymatic activity in each of the cell types tested and, in the case of cat and rat cells, enzymatic expression led to complete normalization of 35SO4 incorporation. In contrast, overexpression of ASB in human MPS VI skin fibroblasts did not lead to metabolic correction. High-level ASB expression was detected for up to eight weeks in transduced MPS VI cat and rat bone marrow cultures, and PCR analysis demonstrated retroviral-mediated gene transfer to approximately 30-50% of the CFU GM-derived colonies. Notably, overexpression of ASB in bone marrow cells led to release of the enzyme into the media and uptake by MPS VI cat and rat skin fibroblasts and/or chondrocytes via the mannose-6-phosphate receptor system, leading to metabolic correction. Thus, these studies provide important rationale for the development of gene therapy for this disorder and lay the frame-work for future in vivo studies in the animal model systems.

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